Developmental Origins of Decreased Resilience

描述（由申请人提供）：孕期母体病毒感染是神经精神疾病和神经发育障碍的危险因素。越来越多的证据表明，母体或胎儿免疫系统在感染期间产生的炎症介质会影响大脑发育，降低日后成功适应急性压力或逆境的能力。弹性较弱的受试者对轻微或无害的压力源会产生夸张或延长的生理和心理反应。因此，在弹性较弱的受试者中，过度的应激反应增加了适应负荷，对身体造成磨损

DESCRIPTION (provided by applicant): Maternal viral infection during pregnancy is a risk factor for neuropsychiatric disease and neurodevelopmental disorders. Mounting evidence indicates that inflammatory mediators produced by the maternal or fetal immune system during infection affect brain development, reducing the ability to adapt successfully to acute stress or adversity later in life. Less resilient subjects experience exaggerated or prolonged physiological and psychological responses to mild or innocuous stressors. Thus, the exaggerated stress response in less resilient subjects adds to the allostatic load, creating wear-and-tear to the body and brain, and ill health. Whereas in humans, this may lead to neuropsychatric problems, in agricultural animals it negatively impacts animal well- being, reduces production efficiency, and leads to pre- and post-slaughter losses. The developmental origins of the loss of resilience owing to maternal infection during pregnancy are poorly understood but recent studies in rodent models suggest infection during an early sensitive period when the brain is experiencing rapid growth sensitizes microglial cells, making them hyper responsive to insults later in life. Extrapolating findings of immune effects on neurodevelopment from rodents to gyrencephalic species is complicated, however, due to profound differences in brain development (e.g., chronology) and structure. Indeed, studies in gyrencephalic animals to gain insight on the pathogenic origins of neurodevelopmental disorders are considered by many, a top priority for research in this field. Thus, the goal of the proposed research is to investigate the developmental origins of the loss of resilience due to maternal infection during pregnancy in pigs- an agriculturally important animal whose brain is remarkably similar to that of humans with respect to gross anatomical features, overall growth pattern, and maturation. Our specific hypothesis is that maternal infection during pregnancy affects the developmental trajectory of the brain and particularly the microglial cell environment, reducing resilience later. As stress resilience is important to human health and animal agriculture, understanding the developmental origins of decreased resilience has dual purpose with dual benefit. Three specific aims are proposed to address our hypothesis wherein postnatal brain structure and resilience will be studied in piglets born by dams inoculated with PRRSV in the final one-third of pregnancy (i.e., equivalent to the third trimester in humans) when the brain is undergoing rapid growth. Piglets will be studied from 7- to 42-d of age to model humans aged 6-months to 3-years and to represent the stressful transition from the farrowing environment to the post weaning nursery. In Aim 1, we will characterize the effects of maternal viral infection on postnatal (a) microglial cell activation, (b) expression of pro-inflammatory and neurotrophic genes in discrete brain regions, and (c) resilience by assessing the magnitude and duration of the ACTH and cortisol responses to stress and using tests designed to probe several behavioral domains including learning and memory, anxiety, frustration, and sociability. In Aim 2, because the fetal brain experiences rapid growth and development during and after the time pregnant gilts will be infected, here we will determine how maternal infection affects structural brain development, first by quantitative MRI in a longitudinal study design; and second using Golgi-Cox staining procedures and Neurolucida to generate three-dimensional tracings for determining the structure of neurons in brain regions corresponding to the behavioral domains under investigation. Finally, in Aim 3, we will determine if reducing microglial cell activity in piglets from virally-infected pregnancies protects brain development and resilience. We propose a clinically relevant scheme using minocycline, a second-generation tetracycline that inhibits neuroinflammation by blocking activation of microglia.